The present invention relates to a series of novel acylaminoquinazoline derivatives having valuable antihypertensive activities, to a process for preparing these derivatives and to pharmaceutical compositions containing these derivatives.
A variety of quinazoline derivatives, including some piperazinyl- and homopiperazinyl-quinazoline derivatives, are known and many of these are known to have hypotensive (or antihypertensive) activity. For example, various such derivatives are described in U.S. Pat. Nos. 3,511,836, 4,060,615, and 3,920,636 and a number of these compounds have been proposed for use as hypotensive agents, and similar compounds are described in copending U.S. application Ser. No. 233,679, filed Feb. 11, 1981, now U.S. Pat. No. 4,426,382 by Y. Sato et al.
In practice, however, only one of these known quinazoline derivatives has actually been used. This compound, which is one of the compounds disclosed in U.S. Pat. No. 3,511,836, is known by the name "prazosin" and has the formula: ##STR2##
Cushman et al. [Science, 196, 441 (1977)] have reported that 1-(D-3-mercapto-2-methylpropanoyl)-L-proline, which, of course, belongs to a wholly different class of compound from the quinazoline derivatives discussed above, shows potent inhibitory activity against the angiotensin I-converting enzyme and, as a result of this inhibitory activity, exhibits antihypertensive activity in hypertensive animals.
Accordingly, we have investigated the possibility of combining the antihypertensive activity characteristic of the piperazinyl- and homopiperazinyl-quinazoline derivatives discussed above with the angiotensin I-converting enzyme inhibitory activity characteristic of 1-(D-3-mercapto-2-methylpropanoyl)-L-proline. In piperazinyl- and homopiperazinyl-quinalzoline derivatives where the nitrogen atom at the 4- position of the piperazine or homopiperazine ring is unsubstituted, reacting the quinazoline derivative with the proline derivative results in acylation of the quinazoline derivative both at the nitrogen atom of the piperazone or homopiperazine ring and at the free amino group which is normally present on the 4- position of the quinazoline system. Accordingly, we have found that, in order to achieve an active compound, it is necessary that the nitrogen atom in the 4- position of the piperazine or homopiperazine ring should be protected; we have also found that the most satisfactory compounds are produced using different proline derivatives from the 1-(D-3-mercapto-2-methylpropanoyl)-L-proline referred to above.